Recent scientific and clinical interest in combining therapeutic agents for the treatment of alcoholism are based on the fact that derangement of multiple-neurotransmitter systems are likely to underlie biological predisposition to the disease. Thus, combining effective medications working at different neurotransmitters should produce a synergistic or at least an added clinical response. We have shown that ondansetron (a serotonin-3 antagonist), compared with placebo, significantly reduces drinking and increases abstinence among EOA but not LOA, presumably by ameliorating an underlying biological (i.e. serotonergic) abnormality which is associated with early onset alcoholism. That is, treatment with the specific serotonergic agent, ondansetron, results in improved drinking outcomes only for a particular alcoholic subtype. In a preliminary clinical trial, we also have shown that topiramate (a sulfamate fructo-pyranose derivative) is superior to placebo at improving the drinking outcomes of both EOA and LOA. We have postulated that topiramate's effectiveness is associated with amelioration of the neurochemical processes due to chronic drinking which occur in both EOA and LOA: notably reduction of generalized craving symptoms due to facilitation of gamma amino butyric acid (GABA) function and inhibition of voltage-gated calcium channels. We, therefore, hypothesize that: 1) the combination of ondansetron and topiramate effects would be additive and possibly synergistic, among EOA; 2) EOA, compared with LOA, will be more responsive to treatment with ondansetron alone, and 3) that both EOA and LOA will respond to topiramate treatment. We will test the specific predictions of this hypothesis by examining the effectiveness of ondansetron (4 mcg/kg b.i.d.) and topiramate (up to 300 mg/day), each alone and in combination, in treating EOA and LOA (45 subjects/cell x 8 cells, total N=360) in a randomized, double-blind, placebo-controlled, 12-week (1 week of single-blind placebo followed by 11 weeks of double-blind condition) outpatient clinical trial. All subjects will receive manual-driven standardized Cognitive Behavioral Therapy, and follow-up at 1, 3, 6, and 9 months post-treatment. This study supports NIAAA's mission to develop effective combinative pharmacotherapies as adjuncts to psychotherapy for the treatment of alcoholism.